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Investigation of Mammalian Retinal Neuron Development

哺乳动物视网膜神经元发育的研究

基本信息

批准号：
9063840
负责人：
Nadean L Brown
金额：
$ 45.61万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063840
关键词：
ATOH7 gene Address Adopted Adult Affect Alagille Syndrome Animal Model Anophthalmos Apoptosis Biochemical Bioinformatics Biological Assay Brain Cell Differentiation process Cell Line Cell Maintenance Cell Proliferation Cells Childhood Chimeric Proteins Coloboma Complex Confocal Microscopy Data Deformity Development Disease EMSA Embryo Embryology Embryonic Development Exhibits Eye Eye Development Figs - dietary Flow Cytometry Gene Targeting Genes Genetic Epistasis Glaucoma Goals Grant Heart Histology Human Immunohistochemistry In Situ Hybridization Inherited Investigation Knowledge Leber&apos s amaurosis Liver Malignant Neoplasms Methods Microphthalmos Molecular Morphogenesis Mouse Strains Mus Mutant Strains Mice Mutation Neurons Notch Signaling Pathway Optic Disk Optic Nerve Optic Neuritis Optics Osteogenesis Pathogenesis Pathway interactions Patients Phenocopy Phenotype Photoreceptors Primary Open Angle Glaucoma Process Publishing Regulation Research Research Project Grants Resources Retina Retinal Retinal Cone Retinal Diseases Retinal Ganglion Cells Role Signal Transduction Site Stem cells Technology Testing Time Transcription Repressor/Corepressor Transgenic Organisms Work developmental genetics eye formation genetic risk factor genome wide association study human disease in vivo mouse model mutant neurogenesis neuron development next generation sequencing notch protein optic nerve disorder optic stalk prenatal public health relevance research study response retinal neuron retinal progenitor cell transcription factor transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates the underlying causes of human ocular diseases using mouse models, focusing on both the Notch signaling pathway, which is broadly required during development, and two classes of bHLH transcription factors (Atoh7/Neurog2 or Hes genes). The activities of both types of factors are regulated by Notch signaling, in particular developmental contexts. The Notch pathway is also responsible for regulating cell proliferation, morphogenesis, differentiation, apoptosis and stem cell maintenance. Dominant mutations in the human Notch pathway genes JAG1 and NOTCH2 cause Alagille syndrome, in which some patients exhibit eye deformities. This proposal will use complex conditional (cre-lox) mouse strains, including double and triple mutants, histology, immunohistochemistry, confocal microscopy, in situ hybridization, mouse embryology, flow cytometry, NEXTgen sequencing, bioinformatics, ChIP, qPCR, and PCR technologies to address basic, mechanistic questions about retinal neuron formation. We will address two important questions, namely 1) Which genes regulate optic nerve head development and maintain the boundary between the retina and optic stalk? 2) What controls retinal progenitor cell differentiation into either a retinal ganglion cell or a cone photoreceptor neuron?

描述（由申请人提供）：本提案使用小鼠模型研究人类眼部疾病的根本原因，重点关注发育期间广泛需要的Notch信号通路和两类bHLH转录因子（Atoh 7/Neurog 2或Hes基因）。这两种类型的因子的活动受Notch信号传导调节，特别是在发育背景下。Notch通路还负责调节细胞增殖、形态发生、分化、凋亡和干细胞维持。人类Notch途径基因JAG 1和NOTCH 2的显性突变导致Alagille综合征，其中一些患者表现出眼睛畸形。该提案将使用复杂的条件（cre-lox）小鼠品系，包括双突变和三突变，组织学，免疫组织化学，共聚焦显微镜，原位杂交，小鼠胚胎学，流式细胞术，NEXTgen测序，生物信息学，ChIP，qPCR和PCR技术来解决有关视网膜神经元形成的基本机制问题。我们将解决两个重要的问题，即1）哪些基因调节视神经乳头的发育和维持视网膜和视柄之间的边界？2)是什么控制视网膜祖细胞分化为视网膜神经节细胞或视锥感光神经元？